Basic esters of alpha-carboxy aryl penicillins

ABSTRACT

ARYLCHLORO (AND BROMO) CARBONYL KETENES, ARYLCARBOXY KETENE BASIC ESTERS DERIVED THEREFROM, METHODS FOR THEIR PREPARATION AND THE USE OF THE ESTERS AS ACYLATING AGENTS FOR THE PRODUCTION OF BASIC ESTERS OF A-CARBOXY ARYL ACETYL DERIVATVES OF 6-AMINOPENICILLANIC ACID AND, BY HYDROLYSIS, THE CORRESPONDING ACID DERIVATIVES, ARE DESCRIBED.

United States Patent 3,631,056 BASIC ESTERS OF a-CARBOXY ARYL PENICILLINS Kenneth Butler, Old Lyme, C0nn., assignor to Pfizer Inc., New York, N.Y.

No Drawing. Continuation-impart of application Ser. N 0. 695,889, Jan. 5, 1968. This application June 4, 1969, Ser. No. 830,517

Int. Cl. C0711 99/16 US. Cl. 260-239.1 13 Claims ABSTRACT OF THE DISCLOSURE Arylchloro (and bromo) carbonyl ketenes, arylcarboxy ketene basic esters derived therefrom, methods for their preparation and the use of the esters as acylating agents for the production of basic esters of a-carboxy aryl acetyl derivatives of 6-aminopenicillanic acid and, by hydrolysis, the corresponding acid derivatives, are described.

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation-in-part of my copending application Ser. No. 695,889, filed Jan. 5, 1968 and now abandoned.

BACKGROUND OF THE INVENTION This invention relates to a series of novel arylchloro (and bromo) carbonyl ketenes; to novel arylcarboxy ketene esters derived therefrom, to the use of the esters as novel acylating agents for the acylation of amines such as 6-aminopenicillanic acid, and to the novel acyl amines thus produced.

The production of ketenes from malonic acid derivatives is described in the literature: Staudinger, Helv. Chim. Acta 8, 306 (1925 prepared a series of low-molecular weight dialkyl ketenes by the thermal decomposition of di( lower)a1kyl substituted malonic anhydrides; Staudinger et al.: Ibid, 6, 291 (1923) and Ber. 46, 3539 (1913) pro duced various disubstituted ketenes by thermal decomposition of mixed anhydrides prepared from disubstituted malonic acids and diphenyl ketene. A still further method comprises the dehalogenation of u-halo acyl halides with zinc (Staudinger, Ann. 356, 71 (1907); 380, 298 (1911)). By extension of this reaction, Staudinger et al., Ber. 42, 4908 (1909) prepared ethyl carbethoxy ketene by the dehalogenation of diethyl-u-bromo-a-ethyl malonate. Another method, the decomposition of diazo ketones, has been used to prepare certain diaryl ketenes (Smith et al., Org. Syntheses 20, 47, 1940; 'Gilman et al., Rec. trav. chim., 48, 464, 1929). It is further known that certain disubstituted acetyl chlorides undergo dehydrohalogenation under the influence of tertiary amines to form keto ketenes. This method, however, appears to be limited to the preparation of certain aryl and high-molecular weight keto ketenes, all of which are relatively resistant to dimerization (Staudinger et al., Ber. 41, 594, 1908).

The reaction of phenylmalonic acid with phosphorus pentachloride (1:2 molar ratio) in ether solution is reported by Sorm et al. (Collection Czechoslov. Chem. Communs. 20, 593-6, 1955)) to produce phenylmalonyl chloride. The same authors report (loc. cit.) that when the reaction is conducted in the absence of a solvent at the reflux temperature, phenylchloromalonyl chloride is produced. Both products are isolated by vacuum distillation.

3,631,056 Patented Dec. 28, 1971 The preparation of lower alkyl esters of phenylcarboxy ketene by thermal decomposition of diazoketo esters has been described by Staudinger et al. (Ber. 49, 2522, 1916). However, the method used by Staudinger is rather complex and results, on an overall basis, in rather poor yields. The process of the present invention for making such esters, on the other hand, is simple and productive of satisfactory yields.

The use of ketenes as actylating agents is well known in the art. The acylation of amino groups by means of simple or mixed acid anhydrides, acid halides, acid azides, p-thiolacetones, acylated enols and carboxylic acids with carbodiimides is also known in the art (Sheehan, US. Pat. 3,159,617, Dec. 1, 1964). However, the introduction of u-carboxy arylacetyl groups into 6-aminopenicillanic acid has, up until now, been limited to the use of a simple or mixed anhydride, an acid halide of an aryl malonic acid or an aryl malonic acid ester as acylating agent (US. Pat. 3,142,673, British Pat. 1,004,670).

The novel esters of the present invention differ from the alkyl esters of a-carboxy-a-arylmethylpenicillins disclosed in the art (South African 67/2804, British 1,004,- 670) in that they are amino substituted alkyl esters characterized by the presence of a secondary or tertiary nitrogen moiety on the alkyl group.

SUMMARY OF THE INVENTION It has now been unexpectedly found that a variety of aryl chlorocarbonyl ketenes, and the corresponding bromo analogs, can readily be prepared by the reaction of aryl malonic acids with a halogenating agent followed by thermal elimination of hydrogen halide and vacuum distillation of the reaction product thus formed. The process and the compounds produced are summarized by the reaction:

COOH

R CH

COOH

wherein R broadly referred to herein as an aryl group, is selected from the group consisting of: thienyl, furyl, pyridyl, phenyl, and substituted phenyl wherein the substituent is selected from the group consisting of (lower)alkyl, chloro, bromo, (lower)alkoxy, di(lower)alkylamino and trifluoromethyl, and X is selected from the group consisting of chloro and bromo.

The process of this invention, in view of the teaching of Sorm et al. (loc. cit.) that phenylmalonyl chloride and phenylchloromalonyl chloride are obtained by the action of phosphorous pentachloride on phenylmalonic acid in the presence of a solvent and the products recovered by vacuum distillation, is more surprising and unexpected. Repetition of the Sorm et al. procedure for making phenylmalonyl chloride has been found to produce phenylchlorocarbonyl ketene rather than phenylmalonyl chloride. The existence of the ketene compound was completely unrecognized by Sorm et al.

The process, in general, comprises reacting an aryl substituted malonic acid with a halogenating agent selected from the group consisting of P(X) P(X) PO(X) and SO(X) wherein X is as defined above at a temperature of from about 0 C. to about 50 C. The dihalide thus produced is thermally decomposed at about 100 C. to provide the aryl halocarbonyl ketene.

The arylhalocarbonyl ketenes exhibit a dual functionality and react both as acid halides and ketenes. They are, therefore, valuable as intermediates for further synthesis. Alcohols (-R OH) for example, react with the arylhalocarbonyl ketenes at low temperatures, e.g. from about 70 C. to about 30 C. to produce the corresponding esters of aryl carboxy ketenes which are useful as acylating agents. Reaction appears to occur first with the ketene group to form a transient intermediate COX R1- :=o-o(oR, owhich rearranges with elimination of hydrogen halide to the arylcarboxy ketene ester.

The novel arylcarboxy ketene esters of this invention are especially valuable as agents for the acylation of amines with production of esters of a-CQIbOXY-oc-HIYI- acetyl amines. They are particularly useful for the acylation of amines such as G-aminopenicillanic acid for the production of known and novel antibacterial agents. Prior art methods for introducing a-carboxyarylacetyl groups into amino compounds such as 6-aminopenicillanic acid have made use of acid anhydrides, mixed or simple, or acid halides of arylmalonic acids. The use of the prior acylating agents requires extreme caution during reaction and recovery steps in order to obtain satisfactory yields and avoid decarboxylation of the carboxy group. The acylating agents of this invention, on the other hand, react smoothly and rapidly with amines at low temperatures and produce no undesirable by-products.

The acid halides and esters of the arylcarboxy ketenes form 3 aryl substituted 2 oxo-oxetenes (1,3-epoxypropenes) in solution. These compounds react in a manner analogous to that of the compounds from which they are derived, and for purposes of this invention are equivalent to said compounds.

The above reactions are summarized in the following sequence:

(I) Rr-E I X wherein R and X are as defined above; and R is selected from the group consisting of:

azetidino aziridino pyrrolidino piperidino morpholino thiomorpholino N-(lower alkyl)piperazino pyrrolo imidazolo 2-irnidazolino 4 2,5-dimethylpyrrolidino 1,4,5 ,6-tetrahydropyrimidino 4-methylpiperidino; 2,6-dimethylpiperidino and R is:

J11ofi owrr O=CN-CHCOOH Of the lower alkyl, lower alkoxy and lower alkanoyl groups those having from 1 to 4 carbon atoms in the alkyl,

alkoxy and alkanoyl moieties are preferred since the reactants bearing such groups are more readily available than are those required for such groups showing a greater number of carbon atoms.

Also included within the scope of this invention are the pharmaceutically-acceptable salts of the novel compounds of Formula III in which one or both acid groups are involved in salt formation. Salts such as the sodium, potassium, calcium, magnesium, ammonium and substituted ammonium salts, e.g., procaine, dibenzylamine, N,N-dibenzylethylenediamine, N,N'-bis-(dihydroabiethyl)ethylenediamine, l-ephenamine, N-ethylpiperdine, Nlbenzyl-B- phenethylamine, trialkylamines, including triethylamine, as well as salts with other amines which have been used to form salts with benzylpenicillin are useful for the preparation of pharmaceutically elegant compositions of these valuable antibiotics.

DETAILED DESCRIPTION OF THE INVENTION The production of arylchloro (and bromo) carbonyl ketenes comprises the reaction of an arylmalonic acid with a halogenating agent selected from the group consisting of P(X) and P(X) and SO(X) wherein X is as defined above at temperatures ranging from about 0 C. to about 50 C. for periods ranging from about one hour to about 10 hours. The reaction is conducted in the presence of a solvent system, preferably a reaction-inert solvent system. Suitable solvents are dialkyl ethers, e.g., diethl ether, dipropyl ether, monoand dimethyl ethers of ethylene glycol and propylene glycol, methylene chloride and chloroform.

The reaction period is, of course, dependent upon the reaction temperature and the nature of the reactants. However, for a given combination of reactants, the lower temperatures require longer reaction periods than do higher temperatures.

The molar proportions of reactants, i.e., arylmalonic acid and halogenating agent, can vary widely, e.g., up to 1:10 or higher, but for satisfactory yields should be at least stoichiometric. In actual practice the stoichiometric ratio of reactants is preferred.

The reactants may be added all once or separately. If separately, the order of addition is not critical. However, it appears that the reaction is smoother and subject to fewer side-reactions, as evidenced by the color of the reaction mixture, particularly upon distillation, when the arylmalonic acid is added to the halogenating agent. The reaction mixture, under such conditions, generally progresses from a yellow to a red color. The reaction mixture on reverse addition, i.e., the addition of halogenating agent to the arylmalonic acid, progresses from yellow to black.

The arylhalocarbonyl ketene products are isolated from the reaction by distillation in vacuo. Because of their great reactivity they are generally stored under a nitrogen atmosphere at low temperatures and in the absence of light.

Reaction of the aryl halocarbonyl ketenes with alcohols is conducted on a 1:1 molar ratio at a temperature of from about 70 C. to about 30 C. when conversion of the aryl halocarbonyl ketene to a ketene ester is desired. A reaction-inert solvent, such as ethyl ether, methyl ether, dioxane, methylene chloride, chloroform, is desirably used to permit better mixing and control of the reaction. The

use of greater than a 1:1 molar ratio of aryl halocarbonyl ketene to alcohol or temperatures above 30 C. produces malonic acid diesters. For example, when two moles of alcohol is used per mole of aryl halocarbonyl ketene the corresponding diester of the arylmalonic acid is produced. Half-amides of arylamalonic acid esters are obtained by reacting the aryl halocarbonyl ketenes with an alcohol followed by reaction of the resulting arylcarboxy ketene ester with a primary or secondary amines as is described herein. Isolation of the intermediate ester is not necessary. A tertiary amine may be used as acid acceptor to remove the hydrogen halide produced during formation of the ester.

The arylcarboxy ketene esters produced as described above are excellent acylating agents particularly suited for the acylation of amines to produce a-carboxyarylacetyl amines. They are especially valuable as agents for the acylation of 6-aminopenicillanic acid.

The acylation of 6-aminopenicillanic acid is conducted at a temperature of from about 70 C. to about 50 C. and preferably at a temperature of from about C. to about 30 C. The reaction period is generally from a few minutes up to about 5 hours. A reaction-inert solvent such as ethyl acetate, dioxane, tetrahydrofuran, methyl isobutyl ketone, chloroform or methylene chloride is generally used to facilitate stirring and temperature control. It has been found especially convenient to first form the arylcarboxyl ketene ester as described above and to use the reaction mixture, without isolation of the arylcarboxy ketene ester, directly in the amine acylation reaction. In such instances an organic base, i.e. a tertiary amine such as triethylamine or other trialkylamine, preferably a tri (lower alkyl) amine, is used to remove the hydrogen halide produced in formation of the arylcarboxy ketene ester. From a practical standpoint, the 6-amin0penicillanic acid is used as its triethylamine salt. For this reason, methylene chloride is a preferred solvent since the triethylamine salt is readily soluble therein. The sodium or potassium salts of 6-aminopenicillanic acid can also be used but the preferred salt is the triethylamine salt because of its greater solubility in the solvent systems used. An excess of the amine to be acylated can, of course, be used as acid acceptor but is generally avoided, not only for economic reasons but also to prevent possible ammonolysis of the ester group. The reaction is desirably conducted under an atmosphere of nitrogen.

The N-acylation reaction can also be conducted in neutral or alkaline aqueous solution by taking advantage of the slower rate of reaction of the arylcarboxy ketene esters with water at neutral or alkaline pH levels relative to the rate of reaction with the amino group. The reaction is conducted at temperatures ranging from just above the freezing point of the aqueous system to about 50 C. and preferably at from 0 to about C. To permit attainment of low temperatures and to facilitate reaction, it is advantageous to employ a mixed solvent system, i.e. water plus a water miscible reaction-inert organic solvent such as dioxane or tetrahydrofuran. The ketene ester is, of course, desirably used as a solution in the same reactioninert solvent and is preferably added to the aqueous solution of the 6-aminopenicillanic acid.

The acylated products are isolated by conventional methods. A typical method, for example, comprises evaporating the reaction mixture to dryness under reduced pressure, dissolving the residue in citrate buffer (pH 5.5) and extracting the product therefrom with chloroform. The chloroform extracts are washed with citrate buffer (pH 5.5), dried with anhydrous sodium sulfate and evaporated to dryness. In another method, which is of value for the isolation of acylation products poorly soluble in methylene chloride, or chloroform, the above method is followed but using n-butanol as extracting solvent in place of chloroform. The product remaining after removal of the n-butanol solvent by evaporation is triturated with ether to prodce an amorphous solid.

In still another method, essentially a variation of the above methods, saturated sodium bicarbonate (or potassium bicarbonate) is used in place of the citrate buffer. This method, of course, produces the sodium (or potassium) salt of the acylation product. If necessary, to obtain a solid product, the salt is triturated with ether.

In yet another method, the residue remaining after removal of the volatiles from the reaction mixture is taken up in water at pH of from about 2.3 to 2.9, usually about pH 2.7, and the free acid form of the acylation product extracted from the acid solution with chloroform, ether, n-butanol or other suitable solvent. The chloroform, ether or n-butanol extract is then washed with aqueous acid (pH 2.32.9) and the product recovered by lyophilization or by conversion to a solvent-insoluble salt as by neutralization with an n-butanol solution of sodium or potassium 2-ethyl-hexanoate.

The esters are converted by known methods to the corresponding acids as, for example, by mild acid treatment or enzymatically with an esterase such as liver homogenate.

The valuable products of this invention are remarkably elfective in treating a number of susceptible gram-positive and gram-negative infections in animals, including man. For this purpose, the pure materials or mixtures thereof with other antibiotics can be employed. They may be administered alone or in combination with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. For example, they may be administered orally in the form of tablets containing such excipients as starch, milk sugar, certain types of clay, etc., or in capsules alone or in admixture with the same or equivalent excipients. They may also be administered orally in the form of elixirs or oral suspensions which may contain flavoring or coloring agents, or be injected parenterally, that is, for example, intramuscularly or subcutaneously. For parenteral administration they are best used in the form of a sterile aqueous solution which may be either aqueous such as water, isotonic saline, isotonic dextrose, Ringers solution, or nonaqueous such as fatty oils of vegetable origin (cotton seed, peanut oil, corn, sesame) and other non-aqueous vehicles which will not interfere with the therapeutic efficiency of the preparation and are non-toxic in the volume or proportion used (glycerol, propylene glycol, sorbitol). Additionally, compositions suitable for extemporaneous preparation of solutions prior to administration may advantageously be made. Such compositions may include liquid diluents, for erample, propylene glycol, diethyl carbonate, glycerol, sorbitol, etc.; buffering agents, as well as local anesthetics and inorganic salts to afford desirable pharmacological properties.

The oral and parenteral dosage levels for the herein described compounds are, in general, on the order of up to 200 mg./kg. and rng./kg. of body weight per day, respectively.

Many of the penicillin ester compounds of this invention exhibit improved absorption on oral administration over that produced by the corresponding free acid or alkali metal salt forms. They, therefore, represent convenient and effective dosage forms of the wcarboxy aryl penicillins.

Additionally, many of the esters described herein, although inactive or of relatively low activity against gramnegative organisms per se, are metabolized to the parent terally into the animal, including the human body. The acid, i.e., a-carboxybenzylpenicillin, when injected parenrate of metabolic conversion of such esters to the parent acid occurs at such a rate as to provide an effective and prolonged concentration of the parent acid in the animal body. In effect, such esters act as depot sources for the parent acid. Especially useful in this respect are those compounds wherein the ester group is COOCH CH Y wherein Y is a basic group such as di(lower alkyl) amino,

pyrrolo, pyrrolidino, piperidino, Z-imidazolino and diisopropylarnino.

The antimicrobial spectra of several esters of a-carboxybenzyl penicillin against Staphylococcus aureus 5 and Escherichia coli 266 are presented in Table I. The tests 5 R2 were run under standardized conditions in which nutrient 0000000000000000000 000 00000 000 1.100 8136.10 55287547 m82smqizooln mmmnzfilmwmmw m mm 2 333 33 333 75 B.P. 80-88 C. at 1.5-2.0 mm. and 74 C. at 0.2 mm.

(C) To a stirred solution of phosphorous pentachloride (46 g.) in ethyl ether (100 m1.) there is added phenylrnalonic acid (10 g.) over a two-minute period. The mixture is stirred at room temperature for four hours then refluxed for four hours and allowed to stand overnight at room temperature. The excess phosphoous pentachloride is filtered off and the ether boiled ofi at atmosphere pressure. The reaction mixture gradually progresses in color from dark yellow to red. The residue is distilled in vacuo to give the product: B.P. 83-86 C. at 1.5 mm. as a yellow liquid.

(D) Repetition of this procedure but using an equivalent amount of phosphorus oxychloride as halogenating agent in place of phosphorous pentachloride produces the same product.

EXAMPLE II The procedure of Example I-C is repeated but using the appropriate malonic acid derivative in place of phenylmalonic acid to produce the following compounds.

S-furyl 2-pyridyl 2-thienyl 3-pyridyl 3-thienyl 4-pyridyl 2-furyl o-bromophenyl o-tolyl m-bromophenyl m-tolyl o-chlorophenyl p-tolyl p-chlorophenyl o-methoxyphenyl m-methoxyphenyl p-methoxyphenyl o-trifluoromethylphenyl p-trifluoromethylphenyl m-trifluoromethylphenyl o-isopropylphenyl p-di- (n-propyl) aminophenyl EXAMPLE IH Repetition of the procedures of Examples LC and II but using PBr in place of P01 produces the corresponding bromo compounds.

EXAMPLE 1V Methyl ester of phenylcarboxy ketene m-chlorophenyl o-butoxyphenyl o-dimethylaminophenyl o-diethylaminophenyl m-dimethylarninophenyl p-dimethylaminophenyl o-dibutylaminophenyl To a solution of phenylchlorocarbonyl ketene (0.5 g.) in dry chloroform (5 ml.) there is added anhydrous methanol (0.1 ml.) at room temperature. Hydrogen chloride is liberated. The mixture, maintained under an atmosphere of nitrogen, is stirred for 20 minutes and the product recovered by evaporation of the solvent.

EXAMPLE V A mixture of phenylmalonic acid (5 g.) and thionyl chloride (30 ml.) is heated to reflux for six hours to give a clear yellow solution. Removal of the excess thionyl chloride by evaporation provides the crude phenylchlorocarbonyl ketene. The pure compound is obtained by distillation in vacuo.

EXAMPLE VI Esters of arylcarboxy ketenes.General preparation method The compounds thus prepared are presented below.

0: O R, R2:

Z-dimethylaminoethyl 2-dibutylaminoethyl 2-diisopropylaminoethyl 3-diisopropylaminopropyl 3 -diethylaminopropy1 2-diethylamin0ethyl 2-di- (n-propyl aminoethyl 3-di-methyla1ninopropyl 3-di- (n-propyl) amino-Z-propyl 2- 2,5 -dimethylpyrrolidino ethyl 2- (4-methylpiperidino ethyl 3-piperidinopropyl 3-pyrrolidino-2-propy1 3-piperidino-2-propyl 2- (2-imidazolino ethyl 3- 2-in1idazolino propyl 2-piperidinoethyl 2-morpholinoethyl 3 -morpholinopropyl 3 -thiomorpholinopropyl 2-pyrrolidino ethyl 2-pyrroloethyl 2-N-methylpiperazinoethyl 3-N-butylpiperazinopropyl 2-( 1,4,5 ,G-tetrahydropyrimidino) ethyl 3-dimethylarnino-2-propyl 2-diethylaminol-propyl 2- (N-methylanilino ethyl 2-N-methyl-N-formylaminoethyl 2-N-methyl-N-acetylaminoethyl 2-N-ethyl-N-formylaminoethyl Z-N-ethyl-N-acetylaminoethyl 2-N-isopropyl-N-f0rmy1aminoethyl 2-N-isopropyl-N-acetylaminoethyl 2-N- n-butyl) -N-formylaminoethyl 2-N- (n-butyl -N-acetylaminoethyl 3-N- (isopropyl -N-formylaminopropyl 3-N- (isopropyl) -N-acetylaminopropyl Z-N-methyl-N-carbomethoxyaminoethyl Z-N-methyl-N-carbo isobutoxy) aminoethyl 2-N-ethyl-N-carb omethoxyaminoethyl 2-N-ethyl-N-carbo isobutoxy) aminoethyl Z-N- n-butyl -N-carbomethoxyaminoethyl 3-N-formylaminopropyl 3-N-acetylaminopropyl 3-N-carbo (isobutoxy aminopropyl 3-N-isopropyl-N-carbo (isobutory) aminopropyl 3-piperidyl 3-( l-methylpiperidyl) 3 1 -butylpiperidyl) 3- l-benzylpiperidyl) The infrared spectre of several of the phenylcarboxyketene esters listed above are presented below (Table III) TABLE III 2-dirnethylaminoethyl 1,720, 1,740, 2,130, 2,960, 3,035 2-(liethy1amin0ethyl 1,720, 1,740, 2,130, 2,960, 3,035 2-di(n-pr0py1)amin0ethyl 1,720, 1,740, 2,130, 2,960, 3,035

2 di (isopropybaminoethyL. 1,720, 1,740, 2,130, 2,960, 3,035 Z-di-(n-butyDaminoethyl 1,720, 1,740, 2,130, 2,960, 3,035 3-dimethylamin0propyl 1,474, 51,640, 1,730, 1,750, 2,130, 2,960, 3-di-(n-propyl)amino2propyl 1,720 1740 2,130 2960 3035 2pyrrolidinoethyl 1 5 00 10001 1,725, 1,750, 2,130, 2,900, 2-piperidinoethyl 1,740, 2,130, 2,960, 3,035 2-morpholinoethyl 1,720, 1,740, 2,130, 2,960, 3,035 2-(2,5dimethylpyrrolidino)ethyl 1,720, 1,740, 2,130, 2,960, 3,035 2-(4-methylpiperidino) ethyl 1,720, 1,740, 2,130, 2,960, 3,035 3-(pyrrolidino)propyl ,720, 1,740, 2,130, 2,300, 3,035 3-pipe1'idinopr0pyl 1,720, 1, 0, 2,130, 2,960, 3,035 3-morpholinopropyl 1,720, 1,740, 2,130, 2,900, 3,033

TABLE III-Continued R2 LR.

3-pyrr0lidin0-2 pr0pyl 1,720, 1,740, 2,130, 2,000, 3,035

3-p1per1d1u0-2-pr0pyl 1,720, 1,740, 2,130, 2,960, 3,035

2-az1r1dmoetl1yl 3,0235, 2,9505 2,880, 2,550, 2,400, 2,325,

2-pyrr0l1d111c-1-pr0pyl 312252501505; 2,880, 2,520, 2,300(Br.),

2 az0tidin0e1hyl 3,012, 2,041, 2,703, 2,315, 2,110, 1,748,

1,630,1, 7,1,403,1,430 2-p1per1d1n0-1-pr0pyl 3,025, 2,050, 2,860, 2,600, 2,420,

2,30003), 2,120, 1,7, 1,010, 1,440 2-(2,0-d1n1cthyl p1pcr1(li11o)ethyl 3,020, 2,040, 2,800, 2,525, 2,3 003),

2, 0, 1,725, 1,480, 1,440 2-morph0l1uo-l-propyl 3,020, 2,070, 2,870, 2,440, 2,220(B),

' 2,130, 1,735, 1,480, 1,440 2-d1(n-pr0pylam1n0)-1-pr0pyl 3,020, 2,070, 2,) 0, 2,870, 2,550,

2,300(B), 2,120, 1,725, 1,480, 1,450 3-d1methylam1n0-2-pr0pyl 3,020, 2,05 B), 2,300(B), 2,130, 1,735 3 m0rph0l1u0-2-propyl .1 3,025, 2040(8), 2,300(B), 2,12

EXAMPLE VII The following additional ketene esters are prepared by the general procedure of Example VI from arylhalo carbonyl ketenes of Examples II and III wherein R is 2-furyl, Z-thienyl, 3-thienyl, 2-pyridyl, 4-pyridyl, p-tolyl, o-methoxyphenyl, p-methoxyphenyl, o-trifluoromethylphenyl, p-chlorophenyl, o-dimethylaminophenyl and pdimethylaminophenyl. For convenience only the R values are listed.

Z-dimethylaminoethyl 2-diisopropylamir1oethyl 3-diethylaminopropyl 2-piperidinoethyl 3-morpholinopropyl 3-thiomorpholinopropyl 2-pyrrolidinoethyl 2- Z-imidazolino ethyl Z-pyrroloethyl 3 -N-methylpiperazinopropyl 2-diethylaminol -propyl 3 -diethylamino-2-propyl 3-morpholir1o-2-propyl 2-( 1,4,5 ,G-tetrahydro pyrimidino) ethyl 3-( l-benzylpiperidyl) 2-N-formylaminoethyl Z-N-methyl-N-formylaminoethyl 3-N-f0rmylaminopropy1 2-N- (n-bu tyl) -N-acetylaminoethyl 2-N-methyl-N-carbomethoxyaminoethyl Z-N-ethyl-N-carbo isobutoxy) aminoethyl 2-N,N-dibenzylaminoethyl 2-N-methyl-N-benzylaminoethyl 3-piperidyl 3-( l-ethylpiperidyl) EXAMPLE VIII Again following the procedure of Example VI, the arylcarboxyketene esters listed below are prepared. The aryl group, R for each of the R values given, is m-tolyl, m-methoxyphenyl, p-trifluoromethylphenyl, 3-pyridyl, o-isopropylphenyl, o-chlorophenyl, o-bromophenyl, mbromophenyl, m-chlorophenyl, o-butoxyphenyl, o-butylphenyl, o-diethylaminophenyl, 3-furyl, m-dimethylaminophenyl, p-di-(n-propyl)aminophenyl and o-dibutylaminophenyl.

Z-dimethylaminoethyl 3-diethylaminopropyl 2-piperidinoethyl 3 -morpho1ino-2-propyl 2-(4-methylpiperidino)ethyl 3-piperidino-2-propyl 2-diethylamino-1-propyl B-diethylamino-Z-propyl 2-morpholinoethyl 3-thiomorpholinopropyl 2-pyrrolidinoethyl 3 -pyrrolopropyl 2-diisopropylaminoethyl 2-( l,4,5,6-tetral1ydropyrimidino ethyl 3 -piperidyl Z-N-acetylarninoethyl 3 -N-acetylaminopropyl Z-N-methyl-N-acetylaminoethyl 2-N-isopropyl-N-formylaminoethyl 2-N,N-dibenzylaminoethyl 3-N-methyl-N-benzylaminopropyl 2-N-methyl-N-carbomethoxyaminoethyl Z-N-methylanilinoethyl 3-( l-benzylpiperidyl) EXAMPLE IX General methods for acylation of 6-aminopenicillanic acid To a solution of the appropriate aryl halocarbonyl ketene (0.1 mole) in methylene chloride (sufiicient to provide a clear solution and generally from about 5 to 10 ml. per gram of ketene) there is added the proper alcohol R OH (0.1 mole). The reaction mixture is maintained under an atmosphere of nitrogen and stirred for a period of from 20 minutes to 3 hours, care being taken to exclude moisture. The temperature may range from about 70 C. to about 20 C. The infrared spectrum of the mixture is then taken to determine and confirm the presence of the ketene ester. A solution of 6-aminopenicillanic acid-triethylamine salt (0.1 mole) in methylenechloride (50 ml.) is added and the mixture stirred at -70 to -20 C. for ten minutes. The cooling bath is then removed and the reaction mixture stirred continuously and allowed to warm to room temperature. The product is isolated by one of the methods below.

Met/10d A.The reaction mixture is evaporated to dryness under reduced pressure and the residue taken up in citrate buffer (pH 5.5 The product is extracted from the buffer solution with chloroform. The chloroform extract is washed with citrate buffer (pH 5.5) then dried with anhydrous sodium sulfate and evaporated to dryness to give the sodium salt.

Method B.-The procedure of Method A is followed but using n-butanol as extracting solvent in place of chloroform. The product obtained after evaporation of the n-butanol solvent is triturated with ether to give an amorphous solid.

Method C.This procedure, a variation of Method A, uses a saturated aqueous solution of sodium (or potassium) bicarbonate in place of citrate buffer to produce the sodium (or potassium) salt of the penicillin product. It is generally used for the recovery of those penicillin products which are poorly soluble in methylene chloride or chloroform.

Met/10d D.The reaction mixture is extracted twice with saturated aqueous sodium or potassium bicarbonate, washed with water, dried and evaporated to dryness to give the sodium (or potassium salt). The product, if not a solid, is triturated with ether.

Method E.-This method, a modification of Method D, is used for those penicillins which are dilficulty soluble in methylene chloride. The sodium (or potassium) bicarbonate solution (Method D) is extracted with n-butanol, the butanol extract dried and evaporated to dryness.

Method F .This method is used to isolate the free acid form of the penicillin.

The residue remaining after evaporation of the reaction mixture to dryness is taken up in aqueous acid, e.g., HCl, at pH 2.7 and the product extracted therefrom by means of n-butanol. The butanol extract is washed with aqueous acid (pH 2.7) and then lyophilized.

Method F-1.The butanol extract of Method F is neutralized with an n-butanol solution of potassium 2- ethyl hexanoate to precipitate the potassium salt of the penicillin.

Method G.-The reaction mixture is evaporated to dryness under reduced pressure, the residue then taken up in ethylacetate-water (1:1) and the pH adjusted to 2.3 with dilute hydrochloric acid. The mixture is thoroughly mixed, the ethylacetate phase separated and added to an equal volume of water. The pH is adjusted to 7.4 with saturated aqueous sodium bicarbonate, the aqueous phase separated and mixed with an equal volume of ethylacetate. The pH is brought to 2.7, the mixture agitated and the ethylacetate layer separated. The extraction is separated and the ethylacetate solutions combined, dried over anhydrous sodium sulfate, then evaporated to dryness under reduced pressure. The residue is taken up in a minimum volume of ethylacetate, one equivalent of N- ethylpiperidine added and the resulting precipitate recovered by filtration or decantation. The product, if noncrystalline, is triturated with ether, filtered, washed with ether and dried.

The N-ethylpiperidine salts are converted to the corresponding sodium salts by treating a benzene solution of the N-ethylpiperidine salt with an acetone solution of sodium ethylhexanoate (1-1 equivalents). The mixture is warmed on a steam bath for five minutes, cooled and the sodium salt precipitated by the addition of a large volume of ether. The product is filtered, washed with ether and dried.

The following compounds are thus prepared:

COORz O: N CH-COOM Method 2-dimethylaminoethyl 3-thiomorpho1inopropyl 2- (1,4,5,6-tetrahydropyrimidino) ethyl 2-(N-methy1) piperazinoethyl 3-N-buty1piperazinopropyl 2-(2,5-dimethyllpyrrolidino) ethyl. 2-aziridinoethy 2-diisobutylam1noethyl B-dimethylaminopropyl 3-di-(n-propy1) ammopropyl Z-thiomorpholinoethyl 2-(4-methy1p1pend1no) ethyl Pyrrolldinornethyl Aziridinomethyl we m m M J- wmmwwwwmaawmawmwmwwamwawgga5gaammgmmaegggggmmmwmwmawwa z 14 TABLE Oon tinued 2-acetamido-1-propyl 2-(methylethylanuno)ethyl Z-(methylbutylarnino) -1-pr0py1. 3-lmidaZo1o-2-propyl 3-az1ridino-2-propy1. 3-pyrrolo-2-propyl s 3-thiomorpholino-2-propy1. 3- (N-methyl) piperaZino-Z-propyl 2-p1peridino-1-propyl e ewwweewwcewwwww NWWNPWINNNNNWEWWWNWNNNNNNWWNWWNNNWWN E 2-N-methyl-N-acetylaminoethyL -N-ethyl-N-formylamino ethyL. -ethyl-N-acetylaminoethyl- -i sopropylN-formy1aminoeth -1sopropyl-N-acetylaminoethyl -(n-butyl)-Nformylaminoethyl -(n-butyl) -N-acetylaminoethyl. s opropyD-N-formylamino -(1sopropyl)-N-aeet -methyl-N-carbomethoxyaminoethyl. -N-methylN-carb0(isobutoxy) aminoethy 2-Nethyl-N -carbomethoxyaminoethyl 2-Nethyl-N-carbo(isobutoxy) aminoethyl. 2-N-(n-butyl) -N-carb omethoxyamlnoethyl 3-N-formylanflnopropyl 3-N-acetylaminopropyl 3-N-carbo(isobutoxy) aminopropyl 3-N-1sopropyl-N-earbo(isobutoxy) amlnopropy 2-N-methyl-N-carbo(isopropoxy) amiuoeth Z-N-ethyl-N-carbo (isopropoxy) amino ethyl 2-N N-dlbenzylaminoethyl 3-N,N-dibenzylaminopropy1 1 N,N-dibenZy1amino-1-prop -N-(n-buty1) -N -benzy1a.m.inoethyl -(n-buty1)-N-butyrylaminoethyl -methyl-N-propionylaminopropyl. -caro omethoxyaminoethyl -b enzyl-N-earbomethoxyaminoethyl. -b enzyl-N-earbo (isopropoxy) aminopr opyl. Z-N-carbobutoxyaminoethyl Z-N-benzyl-N-acetylaminoethyl 3-piperidyl 3-(1-methy1plperidyl) 3-(1-ethy1piperidy1) 3-(l-isopropylpiperidyl 3-(1-11-butylpiperidyl) 3-(1-benzylpiperidyl) F-l ZZZ Z2222 aaaaussa we e e -e e -e e e eve e e e e e e e ewe e'e e e e e e e e m g R Method M 2-(N-methylanilino)ethyl B Na Z-dimethylaminoethyL F1 N a. 2-dibutylaminoethyl. F-l Na 2-d11sopropy1am1noethyl F-l K 3-d1ethy1aminopropyl.- F-l Na 2-(2-imidazolino) eth F H 2-piperidinoethy1. F H 3-morpholinopropyL. F H 3-th1omorpholinopropyl F-1 K 2'pyrrolidinoethyl F-1 K 2-(2-imidazo1ino) ethyl" F-l K 2-pyrroloethy1 F-l K 2-(N-methy1)piperazinoethyl F H Method Method 15 TABLE-Continued TABLE-Continued Method 1'2000OOOCJOOQOOOOOOOOQ'Q'QMM'H LJ-J-HL saeaeaesesaseaseeas 3-piperidino-2-propyl F-l 3-diethylamino-2-propy1- F-l 3-m0rpholin0-2-propyl F-l 3-di-(n-butyl)amino-2-propyl F-l 3-dimethylamino2-pr0pyl F4. 2-(2,6-dimethy1piperidino)ethyl F-l 3-(methylethylamino)propyl F-l 3-piperidinopropyl F-l 3-(N-isopropylanilino)propyl. F-l 3-(N-methylanilino)-2-pr0pyl I 1 Z-(N-methylanilino)-l-propyl F-l EXAMPLE XIII The sodium and potassium salts of Examples IX-XII are converted to the corresponding acids by careful neutralization of aqueous solutions of their salts with aque ous phosphoric acid followed by extraction of the acid form into methylisobutylketone. The methylisobutylketone solutions are washed with Water, dried with anhydrous sodium sulfate, filtered and evaporated to give the free acids.

EXAMPLE XIV The free acids of Examples IX-XIII are converted to their calcium, magnesium ammonium, procaine, N,N'- dibenzylethylenediamine, N-ethylpiperidine, dibenzylamine, l-ephenarnine, triethylamine, N-benzyl-;3-phenethylarnine, N,N' bis(deb.ydroabietyl)ethylenediamine and benzhydrylamine salts by reaction of aqueous solutions thereof with one equivalent of the appropriate base. The salts are recovered by freeze drying.

EXAMPLE XV To a carbo[(Z-N-methylanilino)ethoxy]benzylpenicillin sodium salt (0.1 g.) in chloroform (5 ml.) there is added a solution of citrate buffer (pH 5.5, 5 ml.) and the resulting mixture thoroughly shaken for 7-5 minutes. The aqueous layer is checked every 15 minutes by paper chromatography using the system isoamyl acetatezcitratephosphate buffer (pH 4.5) and bioautographs (Bacillus subtilis).

Wthin 15 minutes ot-carboxybenzylpenicillin is present in the aqueous phase together with a high proportion of the starting ester. After 60 minutes no ester is present in the aqueous phase. The major product observed is OL- carboxybenzylpenicillin. A small amount of benzyl penicillin, its degradation product, is also present.

The a-carboxybenzylpenicillin is isolated by lyophilization and the crude product is further purified by chromatography on Sepadex LH 20 (a cross-linked dextrose available from HB Pharmacia, Uppsala, Sweden).

EXAMPLE XVI A solution of the sodium salt of a-[carbo-(2-di-(npropyl)arnino)-ethoxy]benzyl penicillin in water (0.5 g. in 5 ml.) is held at room temperature for 24 hours. The

pH is automatically regulated at 7.0-7.2 by the addition of sodium bicarbonate. The solution is then freeze dried and the by-product phenol removed by trituration of the residue with ethanol to give the disodium salt.

Repetition of this procedure but at 35 C. for two hours also produces the disodium salt.

EXAMPLE XVII A tablet base is prepared by blending the following ingredients in the proportion by Weight indicated.

Sucrose, U.S.P. 80.3 Tapioca starch 13.2 Magnesium stearate 6.5

Suificient or [carbo(2 di (n-propyl)amino)ethoxy] benzyl penicillin sodium salt is blended into the base to provide tablets containing 25, and 250 mg. of active ingredient.

EXAMPLE XVIII Capsules containing 25, 100 and 250 mg. of active ingredient are prepared by blending sufficient Ot-[Cal'bO(2- morpholino-l-propoxy)]benzyl penicillin sodium salt in the following mixture (proportions given in parts by weight).

Calcium carbonate, U.S.P. 17.6 Dicalcium phosphate 18.8 Magnesium trisilicate 5.2 Lactose, U.S.P. 5.2 Potato starch 5 .2 Magnesium stearate A 0.8 Magnesium stearate B 0.35

EXAMPLE XIX A suspension of oc-[carbo(Z-N-methylanilino)ethoxy] benzyl penicillin sodium salt is prepared with the following composition:

Penicillin compound, g 31.42 70% aqueous sorbitol, g 714.29 Glycerine, U.S.P., g. a- 185.35 Gum acacia (10% solution), ml. 100 Polyvinyl pyrrolidone, g. 0.5 Butyl parahydroxybenzoate, g. 0.172 Propyl parahydroxybenzoate, g. 0.094

Distilled water to make one liter.

Various sweetening and flavoring agents may be added to this suspension, as well as acceptable colors. The suspension contains approximately 25 mg. of penicillin compound per milliliter.

EXAMPLE XX The sodium salt of u-[carbo-(3-di-(n-propyl)amino) propoxy1benzyl penicillin (10 g.) is intimately mixed and ground with sodium citrate (4% by weight). The ground, dry mixture is filled into vials, sterilized with ethylene oxide and the vials sterilely stoppered. For parenteral administration, sufficient water is added to the vials to form solutions containing 25 mg. of active ingredient per ml.

PREPARATION A Malonic acids The following aryl malonic acids not previously described in the literature are prepared by the method of Wallingford et al., J. Am. Chem. Soc. 63, 2056-2059 (1964) which comprises condensing an alkyl carbonate, usually diethyl carbonate, with an equimolar proportion of the desired ethyl aryl acetate in the presence of an excess (4-8 times) of sodium ethylate with continuous removal of by-product alcohol from the reaction mixture. The esters thus produced are hydrolyzed to the acid by known methods.

C O OH R1CH 3-furyl 3-pyridyl o-methoxyphenyl 4-pyridyl m-methoxyphenyl o-butoxyphenyl o-dimethylaminophenyl o-diethylaminophenyl m-dimethylaminophenyl p-dimethylaminophenyl o-dibutylaminophenyl PREPARATION B Aminoisopropanols The following aminoisopropanols are prepared by the reaction of propylene oxide with the appropriate amine. The procedure in general comprises reacting the propylene oxide with an aqueous solution of the amine in a 1.0 to 1.4 molar ratio in a sealed tube. The sealed tube is shaken and allowed to stand overnight, then heated to 80 C. for six hours, then at about 95 C. for four hours. The tube is then cooled, the contents removed and the aminoisopropanol salted out with potassium carbonate.

The product, if liquid, is separated, dried with solid potasium hydroxide then distilled under reduced pressure. The product, if solid, is filtered OH and recrystallized from a suitable solvent. I

4-methylpiperidino 2,5 -dimethylpyrrolidino N-ethylpiperazino N-methylpiperazino aziridino ethylbutylamino methylethylamino ethylisopropylamino methyl propylamino 2,6-dimethylpiperidino azetidino PREPARATION C 2-aminopropanols The following 2-aminopropanols having the formula wherein NR R represents a di(lower alkyl)amino or a heterocyclic group are prepared by the procedure of Motfett, Org. Syn., Coll. vol. IV, p. 834 which comprises lithium aluminum hydride reduction of the appropriate precursor ester of the formula H C OOC-CHNR R0 said esters being prepared as described by Moffett, Org.

Syn, Coll. vol. IV, p. 466 by reaction of the desired amine with ethyl a-bromopropionate.

di (n-propyl amino piperidino di (n-butyl) amino morpholino diisopropylamino thiomorpholino 1,4, 5,6-tetrahydropyrrolo pyrimidino Z-imidazolino N-methylpiperazino imidazolo N-n-butylpiperazino aziridino 4-methylpiperidino pyrrolidino 2,5 -dirnethylpyrrolidino methylbutylamino methylethylamino diethylamino dimethylamino 2,6-dimethylpiperidino azetidino PREPARATION D Aminoethanols N-(fl-hydroxyethyl)substituted heterocyclic amines of the formula HOCH CH NR R are prepared from ethylene oxide by the procedure of Headler et al., I. Am. Chem. Soc. 55, 1066 (1933). This method comprises reacting equimolar quantities of the appropriate heterocyclic amine H-NR R (wherein NR R represents a heterocyclic moiety as defined herein) and ethylene oxide in a copper autoclave at C. for 1-2 hours. The products are recovered by fractional distillation. In this manner the following compounds are prepared:

pyrrolo N-ethyl piperazino pyrrolidino 2,5 -dimethyl)pyrrolidino aziridino (4-mcthyl piperidino morpholino imidazolino thiomorpholino 1,4,5 ,6-tetrahydropiperidino pyrimidino imidazolo methylbutylamino azetidino 2,6-dimethylpiperidino N-methyl piperazino PREPARATION E 3-amino propanols Following the procedure of Pellard et al., J. Org. Chem. 24, 11758 (1959), the following compounds of the formula HOCH CH CH -NR R are prepared.

The method comprises adding 3-chloro-l-propanol (1.0 mole) to a solution of the appropriate amine (2.8 moles) in ethanol (500 ml.) and shaking the mixture thoroughly. The mixture is then refluxed for two hours, potassium hydroxide (1.1 mole) added and the mixture heated for 0.5 hour. Approximately half of the ethanol is distilled off, the mixture cooled and filtered, then distilled further to remove the remaining ethanol and excess amine. The product is recovered by vacuum distillation.

NR R

methylethylamino aziridino methyl-n-propylamino azetidino methyl isopropylamino pyrrolidino methyl-n-butylamino pyrrolo ethyl isopropylamino piperidino ethylbutylamino morpholino n-propyl-n-butylamino thiomorpholino 4-methylpiperidino Z-imidazolino 2,5-dimethylpyrrolidino imidazolo N-methylpiperazino 2,6-dimethylpiperidino PREPARATION F 3 -N-isopropyl-N-carbo(isobutoxy) aminopropanol (A) ('y-chloropropyl)chloroformate.-Phosgene (198 g., 2.0 mole) is slowly bubbled into trimethylene chlorohydrin (188 g., 2.0 mole) at l0-15 C. Nitrogen is then bubbled through the solution for two hours to remove unreacted phosgene. The solution is washed with water fol- 21 lowed by sodium carbonate solution and then fractionally distilled; B.P. 176182 C. at 760 mm.; 243.5 g.

(B) N isopropyl 'y chloropropylcarbamate.-To a stirred solution of isopropylamine (88.5 g., 1.5 moles) in water (250 ml.) t here is added dropwise -chloropropyl)chloroformate (114.5 g., 0.73 mole) over a three hour period. The mixture is stirred for two hours following completion of addition and is cooled in an ice bath. The solid which separates is filtered off, washed with cold water and air dried overnight (128.0 g.)

(C) 3 (N-isopropylamino)propanol.N-isopropyl-'ychloropropylcarbamate (128.0 g., 0.715 mole) dissolved in the minimum volume of ethanol is added to a solution of potassium hydroxide (160.0 g., 2.86 moles) in ethanol (650 ml.). The mixture is refluxed for two hours, then cooled and filtered to remove inorganic salts. The filtrate is swirled with potassium carbonate for fifteen minutes, filtered and evaporated to dryness under reduced pressure. The residue is fractionally distilled; B.P. 5055 C. at 1 mm.

(D) 3 N isopropyl-N-carbo(isobutoxy)aminopropanol.3-N-isopropylaminopropanol (5.5 g., 0.047 mole), ether (15 ml.) and Water (5 ml.) are mixed in a 3-neck, round-bottom flask fitted with stirrer and two dropping funnels. Isobutylchloroformate (6.4 g., 0.047 mole) is added dropwise at C. with vigorous stirring. When onehalf the isobutylchloroformate is added, aqueous sodium hydroxide (1.9 g. in ml. water) is added simultaneously with the last half of the chloroformate. The mixture is stirred at 0 C. for fifteen minutes, then at room temperature for thirty minutes. The ether phase is separated, the aqueous phase extracted with ether m1.) and the combined ether extracts dried with anhydrous sodium sulfate and evaporated. The residue is fractionally distilled; B.P. 158 -162 C. at 11 mm.

In like manner, the following compounds are prepared from the appropriate reactants:

and the pharmaceutically-acceptable salts thereof wherein R is phenyl and R is selected from the group consisting of:

wherein R is selected from the group consisting of, lower alkyl and benzyl; and R is selected from the group con- 22 sisting of lower alkyl, lower alkanoyl, benzyl, phenyl and carbo(lower)alkoxy; and Y is selected from the group consisting of:

pyrrolidino piperidino morpholino 2,6-dimethylpiperidino 2,5-dimethylpyrrolidino 4-methylpiperidino wherein each of lower alkyl, lower alkoxy, and lower alkanoyl have from 1 to 4 carbon atoms, and (lower alkylene) contains from 1 to 3 carbon atoms.

2. The compounds of claim 1 wherein R is CH -CH NR R wherein each of R and R is lower alkyl, and the pharmaceutically-acceptable salts thereof.

3. The compounds of claim 1 wherein R CH CH NR R wherein R is lower alkyl and R is lower alkanoyl and the pharmaceutically-acceptable salts thereof.

4. The compound of claim 1 wherein R is 3-(1-benzylpiperidyl) and the pharmaceutically-acceptable salts thereof.

5. The compound of claim 1 wherein R is wherein each of R and R is benzyl and the pharmaceutically-acceptable salts thereof.

6. The compound of claim 2 wherein R is CH CH N (C H 2 and the pharmaceutically-acceptable salts thereof.

7. The compound of claim 3 wherein R is /CH -CH2-CH2-N and the pharmaceutically-acceptable salts thereof.

8. The compounds of claim 1 wherein R is CH CH -NR R wherein R is lower alkyl and R is phenyl an th e pharmaceutically-acceptable salts thereof.

9. The compounds of claim 1 wherein R is CH(CH CH NR R wherein R is lower alkyl and R is phenyl and the pharmaceutically-acceptable salts thereof.

10. The compounds of claim 1 wherein R is (lower alkylene)Y wherein Y is 2,6-dimethylpiperidino and the pharmaceutically-acceptable salts thereof.

11. The compound of claim 8 wherein R is and the pharmaceutically-acceptable salts thereof.

12. The compound of claim 9 wherein R is and the pharmaceutically-acceptable salts thereof.

13. The compound of claim 10 wherein R is CH -CH -(2,6-dimethylpiperidino) and the pharmaceutically-acceptable salts thereof.

References Cited UNITED STATES PATENTS 3,502,656 3/1970 Neal et al. 260239.1

NICHOLAS S. RIZZO, Primary Examiner U.S. Cl. X.R. 424271 Dedication 3,631,056.-Kemzeth Butler, Old Lyme, Conn. BASIC ESTERS OF a-CAR- BOXY ARYL PEN ICILLIN S. Patent dated Dec. 28, 1971. Dedication filed Mar. 2, 1972, by the assignee,Pfize1" Inc. Hereby dedicates to the Public the entire term of the above-identified patent.

[Ofiioz'al Gazette J uZy 11,1972.] 

